期刊
FOOD AND CHEMICAL TOXICOLOGY
卷 40, 期 8, 页码 1191-1196出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0278-6915(02)00030-3
关键词
vitamin D receptor knockout mouse; 1 alpha-hydroxylase; 8-hydroxy-2 '-deoxyguanosine; colon carcinogenesis
Unimpaired vitamin D action has been implicated in human cancer prevention. We have previously demonstrated the effectiveness of 1alpha-dihydroxyvitamin D3 (1,25-D3) to reduce proliferation and increase differentiation in human colon cancer cells. The aim of this study was to investigate, on the one hand, expression of the vitamin D receptor (VDR) and of 25-hydroxyvitamin D-3-1alpha-hydroxylase (1alpha-hydroxylase) in human normal and malignant colonic tissue and, on the other hand, to determine consequences of reduced or lacking VDR action in, a VDR knockout mouse model. In low-grade malignancies of the human colon we found increased VDR and 1alpha-hydroxylase mRNA expression. However, in late-stage high-grade tumors the vitamin D system is severely compromised. In the mouse colon we found an inverse relationship between VDR levels and proliferation in colon descendens, a tissue known to be specifically affected by nutrients during carcinogenesis. Expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, was significantly augmented with complete loss of VDR. These data suggest that genomic 1,25-D3 action is necessary to protect against nutrition-linked hyperproliferation and oxidative DNA damage. (C) 2002 Elsevier Science Ltd. All rights reserved.
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